Resistance of rectal cancer to radiotherapy manifests as local recurrence, and represents a common but poorly understood problem. Radiation exposure induces apoptosis through diverse signaling pathways, but these death-inducing stimuli can be overriden by powerful cell survival mechanisms termed inducible resistance pathways. Inducible resistance pathways may be abnormally active in some cancers, but these mechanisms have not been studied in the setting of clinical radiotherapy to date. The long-term goal of this project is to better understand the importance of treatment-induced anti-apoptotic signaling in patients being treated with radiation for rectal cancer. This goal will be realized by examining tumor biopsies taken very early after a single fraction of radiation in patients undergoing preoperative therapy. We will analyze signaling pathways with antibodies that are capable of distinguishing the active state of the molecules. We will then perturb these pathways, first in animal models and then in patients, using agents that specifically antagonize the signaling pathways in question. We will then determine the molecular and clinical effects of this perturbation in biopsy samples. Our central hypothesis is that radiation therapy upregulates one or more prosurvival pathways resulting in clinically significant radioresistance and that therapeutic response will be improved by abrogating these signaling responses using targeted drugs. The research projects described form the core of a 5-year career development plan for Dr. Bert O'Neil, an Assistant Professor in the Division of Hematology/Oncology. His mentors, Drs. Joel Tepper, Albert Baldwin, and Richard Goldberg are leaders in the fields of clinical research on Gl malignancies and the basic science of apoptosis and transcriptional regulation. They propose a combined didactic and translational research experience to foster Dr. O'Neil's development into an independent clinician investigator with expertise in the molecular mechanisms of resistance to cancer therapy and apoptosis signaling. They have assembled a carefully selected group of collaborators to assist in the research and in Dr. O'Neil's career development. Rectal cancer is a major health problem whose treatment can result in life-changing morbidity such as the requirement for permanent colostomy as part of therapy. This is partly due to the relative ineffectiveness of radiation on rectal cancer compared with other cancer types, a phenomenon we are trying to better understand via this proposal. The long-term goal of our research is to apply drugs that target tumor but not normal tissue in addition to radiation to improve the effectiveness of radiation on rectal cancer.